Lyme disease is distributed worldwide and has become the most common arthropod borne infection in the United States. Borrelia burgdorferi, the spirochetal agent of Lyme disease, cause several different clinical conditions during human infection. The most common sequelae are disorders of the skin, heart, nervous system, muscles and joints. B. Burgdorferi is considered an extracellular pathogen and the factors encoded by this organism which result in disease pathogenesis are only beginning to be understood. It is apparent, however, that the numerous differentially expressed genes/proteins harbored by this organism play a key role in the borrelial enzootic life cycle and are important for maintaining virulence. To identify differentially expressed genes/proteins, we recently generated an animal model which, for the first time, will allow us to identify and characterize polypeptides selectively expressed by B. burgdorferi during human infection. Therefore, we propose to utilize this animal model, in conjunction with the newly released nucleotide sequence of the complete B. burgdorferi genome, to perform an unprecedented global analysis for identifying borrelial genes expressed exclusively during human infection. Additionally, as noted above, B. burgdorferi is spread by the bite of infected ticks, typically Ixodes scapularis. Therefore, we also propose to identify specific polypeptides laboratory by the salivary glands of Ixodes ticks during feeding which should further our understanding with regard to the biology of pathogen transmission to humans by tick vectors. The studies outlined in this proposal should (i) further our present understanding of the parasitic strategies used by the Lyme disease spirochete during human infection, (ii) identify novel Lyme disease virulence determinants, and (iii) allow us to identify, tick-specific molecules which may be utilized to block tick feeding and pathogen transmission to humans.